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Background: Tau assembly produces soluble oligomers and insoluble neurofibrillary tangles, which are neurotoxic to the brain and associated with Alzheimer’s and Parkinson’s diseases. Therefore, preventing tau aggregation is a promising therapy for those neurodegenerative disorders. Objective: The aim of this study was to develop a joint computational/cell-based oligomerization protocol for screening inhibitors of tau assembly. Methods: Virtual oligomerization inhibition (VOI) experiment using molecular dynamics simulation was performed to screen potential oligomerization inhibitors of PHF6 hexapeptide. Tau seeding assay, which is directly related to the outcome of therapeutic intervention, was carried out to confirm a ligand’s ability in inhibiting tau assembly formation. Results: Our protocol was tested on two known compounds, EGCG and Blarcamesine. EGCG inhibited both the aggregation of PHF6 peptide in VOI and tau assembly in tau seeding assay, while Blarcamesine was not a good inhibitor at the two tasks. We also pointed out that good binding affinity to tau aggregates is needed, but not sufficient for a ligand to become a good inhibitor of tau oligomerization. Conclusion: VOI goes beyond traditional computational inhibitor screening of amyloid aggregation by directly examining the inhibitory ability of a ligand to tau oligomerization. Comparing with the traditional biochemical assays, tau seeding activities in cells is a better indicator for the outcome of a therapeutic intervention. Our hybrid protocol has been successfully validated. It can effectively and efficiently identify the inhibitors of amyloid oligomerization/aggregation processes, thus, facilitate to the drug development of tau-related neurodegenerative diseases. 

Abstract Long-duration GRB 200829A was detected by Fermi-GBM and Swift-BAT/XRT, and then rapidly observed by other ground-based telescopes. It has a weak γ -ray emission in the very early phase and is followed by a bright spiky γ -ray emission pulse. The radiation spectrum of the very early emission is best fitted by a power-law function with index ∼−1.7. However, the bright spiky γ -ray pulse, especially the time around the peak, exhibits a distinct two-component radiation spectrum, i.e., Band function combined with a blackbody radiation spectrum. We infer the photospheric properties and reveal a medium magnetization at a photospheric position by adopting the initial size of the outflow as r 0 = 10 9 cm. It implies that the Band component in this pulse may be formed during the dissipation of the magnetic field. The power-law radiation spectra found in the very early prompt emission may imply the external-shock origination of this phase. Then, we perform the Markov Chain Monte Carlo method fitting on the light curves of this burst, where the jet corresponding to the γ -ray pulse at around 20 s is used to refresh the external shock. It is shown that the light curves of the very early phase and X-ray afterglow after 40 s, involving the X-ray bump at around 100 s, can be well modeled in the external-shock scenario. For the obtained initial outflow, we estimate the minimum magnetization factor of the jet based on the fact that the photospheric emission of this jet is missed in the very early phase.